The work is aimed at improving understanding of enzyme mechanisms through the development of potent antimetabolites, termed "transition state analogs), that resemble activated intermediates in the enzymatic transformation of substrates to products. One part of the work is to develop new classes of transition state analogs, for enzymes that have not previously been studied in this way. Current efforts along these lines are being directed toward histone acetylase, enzymes involved in biosynthesis of ether lipids, and various metalloenzymes related to carboxypeptidase A. The other major part of this work is to explore the physical causes and consequences of tight binding of transition state analogs, in order to obtain informaton about the catalytic process itself, and to indicate directions in which structural changes might be made in order to improve the binding of inhibitors.